1. Field of the Invention
The present invention relates to the field of treating coronary artery disease in HIV-1-infected individuals by interfering with Nef-mediated effect on ABCA1. The invention further relates to suppressing HIV infection by stimulating cholesterol efflux from cells by stimulating expression of ABCA1 in HIV-1-infected individuals.
2. Discussion of Background Information
Cardiovascular disease is a leading cause of death and disability among most of the world's population. Atherosclerosis is the major cause of cardiovascular and cerebrovascular disease and it leads to insufficient blood supply to critical body organs resulting for example, in heart attack, stroke and kidney failure. People suffering from hypertension, diabetes, and HIV infection are at especially high risk of developing atherosclerosis.
While the pathogenesis of atherosclerosis is complex and not completely understood, an underlying pathology led to the numerous theories for the cause of atherosclerosis, for example, an increase in serum cholesterol and the accumulation of cholesterol esters in the arterial wall. Foam cells are the key elements of atherosclerotic plaque formation1. These cells form the cholesterol laden core of the plaque which later undergoes necrosis and calcification and can go on to rupture. The reason for accumulation of foam cells and cholesterol in the vessel wall may be dyslipidemia, especially high levels of low density lipoproteins (LDL) and low levels of high density lipoprotein (HDL), and/or impairment of intracellular cholesterol metabolism. Most likely, both mechanisms contribute to increased risk of CAD (coronary artery disease) in HIV-infected patients as HIV infection targets cholesterol metabolism in the cells central to the development of atherosclerosis, i.e., macrophages, while antiretroviral therapy causes dyslipidemia2,3.
Cholesterol efflux is a pathway for removing excessive cholesterol from cells to extracellular acceptors. It plays a key role in maintaining cell cholesterol homeostasis. Impairment of cholesterol efflux leads to accumulation of intracellular cholesterol4 and development of atherosclerosis in animal models5 and in humans6,7.
While previous studies demonstrated that cholesterol is essential for HIV-1 budding and infectivity8-10 and that HIV-1 protein Nef can directly bind cholesterol and transport it to the site of HIV assembly at the plasma membrane11, the significance of Nef in diminishing the expression of ATP binding cassette transporter A1 (ABCA1), the main transporter of cholesterol from cells to extracellular acceptors, and impairing cholesterol efflux, which leads to cholesterol accumulation and formation of foam cells, remains unknown. These previous studies make no mention of Nef as a cause of CAD in HIV-1-infected individuals. No effect of Nef on ABCA1 activity has been previously described. Further, negative relation between the level of ABCA1 expression in a particular cell and infectivity of HIV-1 produced by this cell has not been previously recognized.
The present invention provides these heretofore needed tools, as well as methods for treating CAD in HIV-infected patients by preventing Nef from binding to ABCA1 in HIV-1-infected cells or/and by stimulating expression of ABCA1 thereby simultaneously suppressing HIV replication.